Mg alloys with excellent high-temperature mechanical properties are urgently desired to meet the design requirements of new-generation aircraft. Herein, novel cast Mg-10Gd-2Y-0.4Zn-0.2Ca-0.5Zr-xAg alloys were designed and prepared according to the advantages of multi-component alloying. The SEM and XRD results revealed that the as-cast microstructures contained α-Mg grains, β, and Zr-containing phase. As Ag rose from 0 wt.% to 2.0 wt.%, the grain size was refined from 40.7 μm to 33.5 μm, and the β phase significantly increased. The TEM observations revealed that the nano-scaled γ′ phase could be induced to precipitate in the α-Mg matrix by the addition of Ag. The stacking sequence of lamellar γ′ phases is ABCA. The multiple strengthening phases, including β phase, γ′ phases, and Zr-containing particles, were effectively tailored through alloying and synergistically enhanced the mechanical properties. The ultimate tensile strength increased from 154.0 ± 3.5 MPa to 231.0 ± 4.0 MPa at 548 K when Ag was added from 0 to 2.0 wt.%. Compared to the Ag-free alloy, the as-cast alloy containing 2.0 wt.% Ag exhibited a minor reduction in ultimate tensile strength (7.0 ± 4.0 MPa) from 498 K to 548 K. The excellent high-temperature performance of the newly developed Mg-RE-Ag alloy has great value in promoting the use of Mg alloys in aviation industries.